The overall goal of this project is to develop and improve an existing mouse model of cystic fibrosis (CF) for use in translational research and preclinical drug test protocols. The project is founded on the hypothesis that severity of CF is influenced by interactions between the causative CF mutation and other genes that differ among individuals, and that response to therapeutic intervention is similarly governed by genetic context. The bENaC {Scnnib) mouse model of Cystic Fibrosis (CF) will be the focus of this application. This transgenic mouse model recapitulates sodium hyperabsorption in human CF by transgenic overexpression of the epithelial sodium channel bENaC (hereafter referred to as Scnnib to reflect the official nomenclature for this gene) in the lung. Although some of the variability in human CF lung disease can be attributed to environmental differences and stochastic accumulation of damage from repeated rounds of infection, it has become clear that the genetic background of the individual patient also plays a major role in the disease progression. Just as individual patients with identical molecular mutations in CFTR present widely variable clinical manifestations of lung disease, as described in detail below, it has became evident that genetic background of the mice also alters the presentation of phenotype in the Scnnib model, suggesting the presence of modifying loci in the different inbred lines. Thus, the Scnnib mouse represents an Ideal animal model to both Identify novel modifier genes and pathways of CF lung disease and to demonstrate the effect of genetic background on preclinical outcomes, paving the way for improved protocol design. This proposal is a unique collaboration between The Jackson Laboratory (JAX) and the Cystic Fibrosis Research and Treatment Center at The University of North Carolina at Chapel Hill (UNC) and promises to leverage the powerful mouse genetic resources available at JAX to enhance the translational application of the Scnnib model for the development of new CF treatment strategies. The proposal utilizes tools and inbred strains supported by the Special Mouse Strains Resource (SMSR) and Mouse Mutant Resource (MMR) to both identify novel genetic modifiers of the Scnnib mouse model and develop the model for preclinical testing protocols, supporting the translational research goals of the North Carolina Translational and Clinical Science (TraCS) Institute (an NCRR-supported CTSA). We will also test the specific hypothesis that individual mucin genes contribute to lung disease in this model. Together, these approaches will have a profound impact on the development of therapies for CF and the use of diverse genetic backgrounds in preclinical testing. Public Health Relevance (provided by the applicant): Cystic fibrosis is a genetic condition that afflicts approximately 30,000 patients in the United States, and results in mucus obstruction, airway inflammation, chronic bacterial infections, bronchiectasis and ultimately death. The proposed experiments will seek to utilize a new model of CF and to identify genes and pathways that modulate disease severity, which in turn will serve as alternate future drug targets. Moreover, this work will establish the Scnnib model on diverse genetic backgrounds for preclinical testing of sodium channel blockers. Thus, this work promises to have a major impact on the treatment of patients with CF.